A MAT2A inhibitor, a pharmaceutical composition comprising the same and use thereof

Abstract

Provided are MAT2A inhibitors, pharmaceutical compositions comprising the same, and uses thereof. Specifically, provided is a compound represented by Formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated derivative, or a combination thereof, wherein each variable is as defined herein, and uses of the compound and pharmaceutical compositions comprising the same in the preparation of medicaments for the prevention or treatment of MTAP ‑ / ‑ related cancers.

Description

A cyclic MAT2A inhibitor, a pharmaceutical composition containing the same, and its use Technical Field

[0001] The present invention belongs to the field of medicinal chemistry. More specifically, the present invention relates to a paracyclic MAT2A inhibitor, a preparation method thereof, a pharmaceutical composition containing the same, and applications thereof. Background Art

[0002] Cancer is one of the leading causes of death worldwide. A limitation of commonly used treatments, such as chemotherapy and immunotherapy, is that their cytotoxicity is not confined to cancer cells and can cause adverse reactions in normal tissues. Therefore, new strategies are needed to better target cancer cells.

[0003] Synthetic lethality occurs when two or more genes are simultaneously defective, leading to cell death. However, a defect in only one gene does not lead to cell death. This phenomenon is known as synthetic lethality. The concept of synthetic lethality originated from studies in fruit flies, which found that flies with two specific gene mutations simultaneously could not survive, whereas mutations in either gene alone would not be lethal. Therefore, synthetic lethality could be used to treat tumors with specific mutations. Specifically, some tumors harbor genetic defects compared to normal tissue. By artificially inhibiting a different signaling pathway, tumor tissue becomes more vulnerable while normal tissue is less affected, thereby achieving the goal of selectively killing the tumor. PARP1 inhibitors are recognized as the first anticancer drugs to successfully utilize the concept of synthetic lethality. Because defects in tumor suppressor genes account for the vast majority of tumor-specific mutations, synthetic lethality could lead to more precise anticancer drugs.

[0004] Methionine adenosyltransferase 2A (MAT2A) is a key enzyme in the production of S-adenosylmethionine (SAM) in cells. It catalyzes the conversion of methionine (Met) and adenosine triphosphate (ATP) to SAM. SAM is a major methyl donor in cells. Various methyltransferases catalyze the transfer of methyl groups from SAM to a variety of substrates, including DNA, RNA, and proteins. Protein arginine N-methyltransferase 5 (PRMT5) is one such methyltransferase. Because methylthioadenosine (MTA) is structurally similar to SAM, it competes with SAM and inhibits PRMT5 activity. MTA can be converted to adenosine and 5-methylthioribose 1-phosphate by an enzyme called methylthioadenosine phosphorylase (MTAP), thus maintaining low MTA concentrations in normal cells. Because the MTAP gene is located near the tumor suppressor gene p16 / CDKN2a, it is co-deleted with p16 / CDKN2a in approximately 15% of human cancers. Solid tumors with a high prevalence of MTAP deficiency include gliomas, mesotheliomas, esophageal cancer, bladder cancer, pancreatic cancer, melanoma, non-small cell lung cancer, head and neck cancer, sarcomas, and cholangiocarcinoma. In these co-deficient tumors, MTAP loss leads to the accumulation of MTA. Abnormally elevated MTA inhibits PRMT5 in tumor tissue, making MTAP-deficient tumors more dependent on SAM production. Therefore, inhibiting MAT2A to reduce SAM levels could selectively kill MTAP-deficient tumor cells. MAT2A knockout in approximately 400 cancer cell lines revealed that a greater proportion of MTAP-deficient cells lost viability compared to MTAP-WT cells. Furthermore, knockdown of MAT2A protein reduced tumor growth in vivo. These results suggest that MAT2A inhibitors may provide a new therapeutic approach for patients with MTAP-deficient cancers.

[0005] IDE397 is a MAT2A inhibitor at the forefront of research and development. Preclinical studies have demonstrated significant efficacy in models of non-small cell lung cancer, bladder cancer, pancreatic cancer, head and neck cancer, gastric cancer, and esophageal cancer (AACR 2021). Phase II clinical trials have further demonstrated the compound's efficacy in patients with non-small cell lung cancer and urothelial cancer.

[0006] Therefore, it is urgent to develop a compound with good inhibitory effect on MAT2A for the preparation of MTAP - / - Cancer-related drugs. Summary of the Invention

[0007] The object of the present invention is to provide a novel cyclic compound with good MAT2A inhibitory effect, a pharmaceutical composition containing the same, and uses thereof.

[0008] In a first aspect of the present invention, there is provided a compound of Formula I, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated form, or combination thereof.

[0009] in,

[0010] R 1 is selected from the group consisting of hydrogen, hydroxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, optionally substituted 6-10 membered aryl, optionally substituted 5-10 membered heteroaryl, -L 1 -R 4 and -NR 5 R 6 ; R 1 In the present invention, the term "optionally substituted" means that the specified group is unsubstituted or replaced by one or more R 1s Replaced by, and R 1s Each is independently selected from the following group: halogen, hydroxy, amino, cyano, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 haloalkynyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy C1-C6 alkyl- (i.e. C1-C6 hydroxyalkyl), C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-10 membered carbocyclyl,

[0011] L 1 Selected from the group consisting of -O-, -S-, -SO-, -SO2-, and -CO-;

[0012] R 4 is selected from the group consisting of an optionally substituted C1-C6 alkyl, an optionally substituted 3-10 membered carbocyclyl, an optionally substituted 4-8 membered heterocyclyl, an optionally substituted 6-10 membered aryl, and an optionally substituted 5-10 membered heteroaryl; R 4 In the present invention, the term "optionally substituted" means that the specified group is unsubstituted or replaced by one or more R 4s Replaced by, and R 4sEach is independently selected from the group consisting of halogen, hydroxy, amino, cyano, oxo, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 haloalkynyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy C1-C6 alkyl, amino C1-C6 alkyl, 3-10 membered carbocyclyl, 3-10 membered carbocyclyloxy, 4-8 membered heterocyclyl, 4-8 membered heterocyclyloxy, 6-10 membered aryl, 5-10 membered heteroaryl,

[0013] R 5 Selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and 3-10 membered carbocyclyl;

[0014] R 6 is selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 6-10 membered aryl, optionally substituted 5-10 membered heteroaryl, R 6 In the present invention, the term "optionally substituted" means that the specified group is unsubstituted or replaced by one or more R 6s Replaced by, and R 6s Each independently selected from the group consisting of deuterium, halogen, hydroxy, amino, cyano, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 haloalkynyl, optionally substituted by one or more R 8 substituted 3-10 membered carbocyclic group, optionally substituted by one or more R 8 substituted 3-10 membered carbocyclyloxy, optionally substituted with one or more R 8 substituted 4-8 membered heterocyclic group, optionally substituted by one or more R 8 Substituted 4-8 membered heterocyclyloxy, C1-C6 alkylamino, (C1-C6 alkyl) 2 amino, C1-C6 alkoxy-C1-C6 alkyl, amino C1-C6 alkyl, Optionally, one or more R 9 substituted 6-10 membered aryl and optionally substituted by one or more R 9 substituted 5-10 membered heteroaryl;

[0015] R 2 Selected from: halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, -L2 -R 10 and -NR 11 R 12 ; R 2 In the present invention, the term "optionally substituted" means that the specified group is unsubstituted or replaced by one or more R 2s Replaced by, and R 2s Each is independently selected from the group consisting of halogen, cyano, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and 3-10 membered carbocyclyl;

[0016] R 3 Selected from the group consisting of hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, -L 2’ -R 10’ and -NR 11’ R 12’ ; R 3 In the present invention, the term "optionally substituted" means that the specified group is unsubstituted or replaced by one or more R 3s , and R 3s Each is independently selected from the group consisting of halogen, cyano, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and 3-10 membered carbocyclyl;

[0017] L 2 and L 2’ Each independently selected from the group consisting of -O-, -S-, -SO-, -SO2-, and -CO-;

[0018] R 10 and R 10’ R is independently selected from the group consisting of an optionally substituted C1-C6 alkyl group, an optionally substituted 3-10 membered carbocyclyl group, an optionally substituted 4-8 membered heterocyclyl group, an optionally substituted 6-10 membered aryl group, and an optionally substituted 5-10 membered heteroaryl group; 10 and R 10’ In the present invention, the term "optionally substituted" means that the specified group is unsubstituted or replaced by one or more R 10s Replaced by, and R 10s Each is independently selected from the group consisting of halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-10 membered carbocyclyl, 4-8 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl;

[0019] R 11 and R 11’ Each independently selected from the group consisting of hydrogen and C1-C6 alkyl;

[0020] R 12 and R 12’ Each is independently selected from the group consisting of an optionally substituted C1-C6 alkyl group, an optionally substituted 3-10 membered carbocyclyl group, an optionally substituted 4-10 membered heterocyclyl group, an optionally substituted 6-10 membered aryl group, an optionally substituted 5-10 membered heteroaryl group, R 12 and R 12’ In the present invention, the term "optionally substituted" means that the specified group is unsubstituted or replaced by one or more R 12s Replaced by, and R 12s Each is independently selected from the group consisting of halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-10 membered carbocyclyl and 4-8 membered heterocyclyl;

[0021] X 3 Selected from the group consisting of: CH and N;

[0022] R X Selected from the group consisting of methyl, ethyl, 3-4 membered carbocyclyl, halomethyl or halogen;

[0023] R Y Selected from the group consisting of hydrogen, methyl, halomethyl or halogen;

[0024] X 1 Selected from the following group: CR 13 and N;

[0025] X 2 Selected from the following group: CR 14 and N;

[0026] R 13 and R 14 R is independently selected from the group consisting of hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-8 membered heterocyclyl; 13 and R 14 In the present invention, the term "optionally substituted" means that the specified group is unsubstituted or replaced by one or more R 13s or R 14s Replaced by, and R 13s and R 14s are independently selected from the group consisting of halogen and oxo; provided that, when R X and R 2 At the same time, chlorine and X 1 CR 13 When R 13 Not for chlorine;

[0027] Each R7 Each is independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-10 membered carbocyclyl, 4-8 membered heterocyclyl, amino, C1-C6 alkylamino (i.e., -NH(C1-C6 alkyl)), di(C1-C6 alkyl)amino (i.e., -N(C1-C6 alkyl)2), 6-10 membered aryl, and 5-10 membered heteroaryl;

[0028] Each R 8 Each is independently selected from the group consisting of hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl or hydroxy C1-C6 alkyl;

[0029] Each R 9 Each is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl.

[0030] In another preferred embodiment, R 1 Selected from the group consisting of hydrogen, hydroxy, optionally substituted C1-C6 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, -OR 4 and -NR 5 R 6 Preferably, R 1 Selected from the group consisting of hydrogen, hydroxy, optionally substituted 4-8 membered heterocyclyl or -NR 5 R 6 .

[0031] In another preferred embodiment, R 1 Selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl (preferably C1-C6 alkyl) and -NR 5 R 6 .

[0032] In another preferred embodiment, R 5 Selected from the group consisting of hydrogen and C1-C6 alkyl; preferably, R 5 For hydrogen.

[0033] In another preferred embodiment, R 6 is selected from the group consisting of an optionally substituted C1-C6 alkyl group, an optionally substituted 3-10 membered carbocyclyl group, and an optionally substituted 5-10 membered heteroaryl group; preferably, R 6 Selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl.

[0034] In another preferred embodiment, R 6s are each independently selected from the group consisting of deuterium, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C2-C4 alkynyl, C1-C3 alkoxy, C1-C3 haloalkoxy, and 6-10 membered aryl; preferably, R6s Each is independently selected from the group consisting of deuterium, halogen.

[0035] In another preferred embodiment, R 5 is hydrogen, and R 6 is selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl; and R 6s For deuterium.

[0036] In another preferred embodiment, R 2 is selected from the group consisting of halogen, optionally substituted C1-C6 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, and -L 2 -R 10 .

[0037] In another preferred embodiment, R 2s Each is independently selected from the group consisting of halogen, cyano, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and 3-8 membered carbocyclic group; preferably, R 2s Each is independently selected from the group consisting of halogen, C1-C6 alkyl.

[0038] In another preferred embodiment, R 3 Selected from the group consisting of hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, -L 2’ -R 10’ Preferably, R 3 Selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl.

[0039] In another preferred embodiment, R 3s Each is independently selected from the group consisting of halogen, cyano, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and 3-8 membered carbocyclyl.

[0040] In another preferred embodiment, R 10 and R 10’ Each is independently selected from the group consisting of an optionally substituted C1-C6 alkyl group, an optionally substituted 3-8 membered carbocyclyl group, and an optionally substituted 4-8 membered heterocyclyl group.

[0041] In another preferred embodiment, R 10s Each is independently selected from the following group: halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-8 membered carbocyclyl, 4-8 membered heterocyclyl.

[0042] In another preferred embodiment, R 2Selected from the following groups: halogen (such as F, Cl, Br), optionally substituted C1-C6 alkyl (preferably, C1-C6 alkyl or C1-C6 haloalkyl, more preferably, C1-C6 haloalkyl such as trifluoromethyl), and optionally substituted 3-10 membered carbocyclyl (preferably, 3-10 membered carbocyclyl, more preferably, C3-C6 cycloalkyl, most preferably, selected from cyclopropyl and cyclobutyl).

[0043] In another preferred embodiment, R 3 -L 2’ -R 10’ Among them, L 2’ -O- and R 10’ is an optionally substituted C1-C6 alkyl group (preferably, R 10’ is a C1-C6 alkyl group; more preferably, R 10’ is methyl).

[0044] In another preferred embodiment, R 3 For hydrogen.

[0045] In another preferred embodiment, R 3 is hydrogen or -L 2’ -R 10’ Among them, L 2’ -O- and R 10’ Methyl (ie R 3 is hydrogen or methoxy).

[0046] In another preferred embodiment, R 13 and R 14 Each is independently selected from the group consisting of hydrogen, halogen, cyano, C1-C4 alkyl or C1-C4 haloalkyl.

[0047] In another preferred embodiment, R 13 is hydrogen or halogen (such as F).

[0048] In another preferred embodiment, X 1 CR 13 ; Preferably, CH or CF.

[0049] In another preferred embodiment, X 1 CR 13 ; Preferably, CH.

[0050] In another preferred embodiment, X 2 CR 14 ; Preferably, CR 14 And R 14 Selected from the group consisting of hydrogen, halogen (such as F), C1-C4 alkyl (such as methyl) and optionally substituted 3-10 membered carbocyclic group (preferably 3-4 membered carbocyclic group, more preferably 3-4 membered saturated carbocyclic group, such as cyclopropyl).

[0051] In another preferred embodiment, X 2 CR 14 ; Preferably, CR 14 And R 14 Selected from the group consisting of hydrogen, halogen (such as F), and C1-C4 alkyl (such as methyl).

[0052] In another preferred embodiment, X 3 is N.

[0053] In another preferred embodiment, R X In the embodiment, the 3-4 membered carbocyclic group is a 3-4 membered saturated carbocyclic group; preferably, it is a cyclopropyl group.

[0054] In another preferred embodiment, R X Selected from the group consisting of methyl, ethyl, halomethyl or halogen.

[0055] In another preferred embodiment, R X is methyl, halogen or cyclopropyl.

[0056] In another preferred embodiment, R X is methyl or halogen.

[0057] In another preferred embodiment, R Y is hydrogen, methyl or halogen (such as F).

[0058] In another preferred embodiment,

[0059] R 1 Selected from the group consisting of hydrogen, hydroxy, optionally substituted C1-C6 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, -OR 4 and -NR 5 R 6 ; R 1 The term "optionally substituted" means that the specified group is unsubstituted or replaced by one or more R 1s Replaced by, and R 1s Each is independently selected from the group consisting of halogen, hydroxy, amino, cyano, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy and C1-C6 haloalkoxy.

[0060] In another preferred embodiment, R 1 Selected from the group consisting of hydrogen, hydroxy, optionally substituted 4-8 membered heterocyclyl or -NR 5 R 6; wherein the heterocyclic group is optionally substituted by a substituent selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, hydroxyl and amino;

[0061] R 5 Selected from the group consisting of hydrogen and C1-C6 alkyl;

[0062] R 6 is selected from the group consisting of an optionally substituted C1-C6 alkyl group, an optionally substituted 3-10 membered carbocyclyl group, and an optionally substituted 5-10 membered heteroaryl group; R 6 In the present invention, the term "optionally substituted" means that the specified group is unsubstituted or replaced by one or more R 6s Replaced by, and R 6s Each is independently selected from the group consisting of deuterium, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C2-C4 alkynyl, C1-C3 alkoxy, C1-C3 haloalkoxy and 6-10 membered aryl.

[0063] In another preferred embodiment, R 1 Selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 4-8 membered heterocyclyl or -NR 5 R 6 ; Among them, R 5 is hydrogen, and R 6 is selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, and optionally substituted 5-10 membered heteroaryl; preferably, R 6 In the present invention, the term "optionally substituted" means that the specified group is unsubstituted or replaced by one or more R 6s Replaced by, and R 6s is deuterium or C1-C6 alkyl.

[0064] In another preferred embodiment, R 1 In the example, the 5- to 10-membered heteroaryl group is a 9- to 10-membered heteroaryl group.

[0065] In another preferred embodiment, R 1 In the embodiment of the present invention, the heteroaryl group contains only 1, 2, 3 or 4 N as heteroatoms.

[0066] In another preferred embodiment, R 1 Selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl and -NR 5 R 6 ; Among them, R 5 is hydrogen, and R 6 Selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl.

[0067] In another preferred embodiment,

[0068] R 2is selected from the group consisting of halogen, optionally substituted C1-C6 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, and -L 2 -R 10 ; R 2 In the present invention, the term "optionally substituted" means that the specified group is unsubstituted or replaced by one or more R 2s Replaced by, and R 2s Each is independently selected from the group consisting of halogen, cyano, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and 3-8 membered carbocyclyl;

[0069] R 3 Selected from the group consisting of hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, -L 2’ -R 10’ ; R 3 In the present invention, the term "optionally substituted" means that the specified group is unsubstituted or replaced by one or more R 3s Replaced by, and R 3s Each is independently selected from the group consisting of halogen, cyano, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and 3-8 membered carbocyclyl;

[0070] R 10 and R 10’ Each is independently selected from the following group: optionally substituted C1-C6 alkyl, optionally substituted 3-8 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl; R 10 and R 10’ In the present invention, the term "optionally substituted" means that the specified group is unsubstituted or replaced by one or more R 10s Replaced by, and R 10s Each is independently selected from the following group: halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-8 membered carbocyclyl, 4-8 membered heterocyclyl.

[0071] In another preferred embodiment, R 2 is selected from the group consisting of halogen, optionally substituted C1-C6 alkyl (preferably C1-C6 haloalkyl) and optionally substituted 3-10 membered carbocyclic group. In another preferred embodiment, the 3-10 membered carbocyclic group is a 3-10 membered saturated carbocyclic group; preferably, a 3-4 membered saturated carbocyclic group. In another preferred embodiment, R 2s Each is independently selected from the group consisting of halogen, C1-C6 alkyl.

[0072] In another preferred embodiment, R Xis selected from the group consisting of methyl, ethyl, halomethyl and halogen; X 1 Selected from the following group: CR 13 and N;X 2 Selected from the following group: CR 14 and N; and R 13 and R 14 Each is independently selected from the group consisting of hydrogen, halogen, cyano, C1-C4 alkyl or C1-C4 haloalkyl.

[0073] In another preferred embodiment, the additional condition is that when R X and R 2 At the same time, chlorine and X 1 CR 13 When R 13 Not for chlorine.

[0074] In another preferred embodiment, X 3 Selected from the group consisting of CH and N; R X is methyl or halogen; R Y is hydrogen, methyl or halogen.

[0075] In another preferred embodiment, R 1 、R 2 、R 3 、R X 、R Y 、X 1 and X 2 Each is independently the corresponding group of the specific compound shown in Table A and the Examples.

[0076] In another preferred embodiment, the compound is selected from the following Table A:

[0077] Table A

[0078] In a second aspect of the present invention, a pharmaceutical composition is provided, comprising:

[0079] (1) a therapeutically effective amount of the compound of the first aspect, or one or more of its pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, cis-trans isomers, solvates, polymorphs and deuterated forms as an active ingredient; and

[0080] (2) Optionally, a pharmaceutically acceptable carrier.

[0081] In the third aspect of the present invention, there is provided a compound as described in the first aspect, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph or deuterated compound thereof, or a pharmaceutical composition as described in the second aspect for use in the preparation of a method for preventing or treating MTAP. - / - Use in medicine for treating related cancers.

[0082] In another preferred embodiment, the cancer is selected from the group consisting of glioma, mesothelioma, esophageal cancer, bladder cancer, urothelial carcinoma, pancreatic cancer, melanoma, non-small cell lung cancer, head and neck cancer, sarcoma, bile duct cancer, liver cancer, breast cancer, skin cancer, intestinal cancer, gastric cancer, kidney cancer, urethral cancer, prostate cancer, testicular cancer, uterine cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, multiple myeloma, spinal neurofibroma, astrocytoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma and non-Hodgkin's lymphoma.

[0083] In another preferred embodiment, the MTAP - / - The associated cancers are MTAP-deficient cancers.

[0084] In the fourth aspect of the present invention, there is provided a compound as described in the first aspect, or a pharmaceutical composition as described in the second aspect, for use in preventing or treating MTAP. - / - Related cancers.

[0085] In another preferred embodiment, the cancer is selected from the group consisting of glioma, mesothelioma, esophageal cancer, bladder cancer, urothelial carcinoma, pancreatic cancer, melanoma, non-small cell lung cancer, head and neck cancer, sarcoma, bile duct cancer, liver cancer, breast cancer, skin cancer, intestinal cancer, gastric cancer, kidney cancer, urethral cancer, prostate cancer, testicular cancer, uterine cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, multiple myeloma, spinal neurofibroma, astrocytoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma and non-Hodgkin's lymphoma.

[0086] In another preferred embodiment, the MTAP - / - The associated cancers are MTAP-deficient cancers.

[0087] In a fifth aspect of the present invention, a method for treating or preventing MTAP is provided. - / - A method for treating or preventing MTAP, comprising the steps of administering to a subject in need thereof a therapeutically effective amount of the compound of the first aspect, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph or deuterated form thereof, or the pharmaceutical composition of the second aspect, thereby instructing or preventing MTAP. - / - Related cancers.

[0088] In another preferred embodiment, the cancer is as defined above.

[0089] In another preferred embodiment, the MTAP - / - Related cancers are as defined above.

[0090] In a sixth aspect of the present invention, a method for inhibiting cell proliferation activity is provided, comprising the steps of:

[0091] The cells are contacted with the compound according to the first aspect, thereby inhibiting the proliferation activity of the cells.

[0092] In another preferred embodiment, the method is non-therapeutic in vitro.

[0093] In another preferred embodiment, the cells are cancer cells.

[0094] In another preferred embodiment, the cell is MTAP - / - cells (i.e., MTAP-deficient cells).

[0095] In another preferred embodiment, the cells are selected from the group consisting of: HCT116 MTAP - / - cells, HCC15, NCI-H2052, LN18, NCI-H838, LU99, DOHH2, HT-1080, MKN45, THP-1, MCF7, Mia Paca2, U87MG, UMUC3, or a combination thereof.

[0096] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0097] After extensive and in-depth research, the inventors synthesized a series of novel structural cyclic compounds as shown in Formula I for the first time and tested their biological activity. They unexpectedly found that these compounds have a good inhibitory effect on MAT2A. Therefore, they can be used to prepare a novel compound for the treatment of MTAP. - / - On this basis, the present invention was completed.

[0098] Terminology

[0099] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0100] As used herein, the terms "comprising" or "including" may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0101] Group Definition

[0102] Definitions of standard chemical terms can be found in the references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy and pharmacological methods, are used. Unless otherwise specified, the terms used herein in the descriptions of analytical chemistry, synthetic organic chemistry, and pharmaceuticals and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and in the treatment of patients. For example, the manufacturer's instructions for use of the kit can be utilized, or reactions and purifications can be carried out in accordance with methods well known in the art or the description of the present invention. The above techniques and methods can generally be implemented according to conventional methods well known in the art, as described in the various general and more specific references cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0103] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0104] The section headings used herein are for organizational purposes only and should not be construed as limitations on the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are incorporated herein by reference in their entirety.

[0105] Certain chemical groups defined herein are preceded by a simplified notation to indicate the total number of carbon atoms present in the group. For example, a C1-C6 alkyl group refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the simplified notation does not include carbons that may be present in substituents of the group.

[0106] In addition to the foregoing, when used in the specification and claims of this application, the following terms have the meanings indicated below unless otherwise specifically stated.

[0107] In this application, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0108] "Hydroxy" refers to an -OH group.

[0109] "Hydroxyalkyl" or "hydroxyalkyl" refers to an alkyl group, as defined below, substituted with a hydroxy (-OH) group.

[0110] "Carbonyl" refers to a -C(=O)- group.

[0111] "Nitro" refers to -NO2.

[0112] "Cyano" refers to -CN.

[0113] "Amino" refers to -NH2.

[0114] "Substituted amino" refers to an amino group substituted with one or two alkyl groups, alkylcarbonyl groups, arylalkyl groups, heteroarylalkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkylamido, arylalkylamino, heteroarylalkylamino.

[0115] "Carboxyl" refers to -COOH.

[0116] In this application, as a group or part of other groups (for example, in groups such as halogen-substituted alkyl), the term "alkyl" refers to a fully saturated straight or branched hydrocarbon chain radical consisting only of carbon atoms and hydrogen atoms, with, for example, 1 to 12 (C1-C 12 The term "alkyl" refers to an alkyl group (preferably 1 to 8 (C1-C8 alkyl), more preferably 1 to 6 (C1-C6 alkyl)) carbon atoms, and is connected to the rest of the molecule by one or more single bonds, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl and decyl. For the purposes of the present invention, the term "alkyl" preferably refers to an alkyl group containing 1 to 6 carbon atoms.

[0117] In this application, the term "alkenyl" as a group or part of another group means an alkenyl group consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (C2-C 14 alkenyl) (preferably 2 to 10 (C2-C 10 The present invention also includes a straight or branched hydrocarbon chain group having 2 to 6 (C2-C6 alkenyl) carbon atoms and connected to the rest of the molecule by one or more single bonds, such as but not limited to vinyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl, etc.

[0118] As used herein, the term "alkynyl" as a group or as part of another group refers to an alkynyl group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having, for example, 2 to 14 carbon atoms (C2-C 14 Alkynyl) (preferably 2 to 10 (C2-C 10 Alkynyl), more preferably a straight or branched hydrocarbon chain group of 2 to 6 (C2-C6 alkynyl) carbon atoms connected to the rest of the molecule by one or more single bonds, such as but not limited to ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, etc.

[0119] In this application, the term "carbocycle" as a group or part of another group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon atoms and hydrogen atoms, which may include a fused ring system, a bridged ring system or a spiro ring system, having 3 to 15 carbon atoms (i.e., C3-C 15 or 3-15 membered carbocyclic ring (group), preferably having 3 to 10 carbon atoms (ie C3-C 10 or 3-10 membered carbocyclic ring (radical), more preferably having 3 to 8 carbon atoms (i.e. C3-C8 or 3-8 membered carbocyclic ring (radical), more preferably 3 to 6 carbon atoms (i.e. C3-C6 or 3-6 membered carbocyclic ring (radical), and it is a saturated or unsaturated ring (e.g. cycloalkyl, cycloalkenyl, etc.) and can be connected to the rest of the molecule through one or more single bonds via any suitable carbon atom. Unless otherwise specifically indicated in this specification, the carbon atoms in the carbocyclic group can be optionally oxidized. Examples of carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, 2,3-dihydroindanyl, octahydro-4,7-methylene-1H-indanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, 1H-indenyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocyclohepten-5, 5,6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl, 1,2,3,4-tetrahydro-naphthyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, 1H-indenyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocyclohepten-5, 1,2,3,4-tetrahydro-naphthyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, 1H-indenyl, 6,7,8,9,10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl and octahydro-2,5-methylene-pentalenyl, etc.

[0120] In the present application, as a group or part of other groups, the term "cycloalkyl" (such as "C3-C6 alkyl") refers to the above-mentioned fully saturated carbocyclic ring (radical), typical cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, etc.

[0121] In the present application, as a group or part of other groups, the term "cycloalkenyl" (such as "C4-C6 cycloalkenyl") refers to a partially unsaturated carbon ring (radical). Typical cycloalkenyl groups include but are not limited to cyclobutenyl, cyclopentenyl, cyclohexenyl, etc.

[0122] In the present application, the term "heterocyclic group" as a group or part of another group means a stable 3- to 20-membered non-aromatic cyclic group (i.e., a 3-20-membered heterocyclic group) consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. Unless otherwise specified in this specification, the heterocyclic group can be a monocyclic, bicyclic, tricyclic or more ring system, which can include a fused ring system, a bridged ring system or a spirocyclic system; the nitrogen, carbon or sulfur atoms in the heterocyclic group can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclic group can be partially or fully saturated. The heterocyclic group can be connected to the rest of the molecule via a carbon atom or a heteroatom and by one or more single bonds. In a heterocyclic group containing a fused ring, one or more rings can be an aryl or heteroaryl group as defined below, provided that the point of connection to the rest of the molecule is a non-aromatic ring atom. For the purposes of the present invention, the heterocyclic group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur (i.e., a 4-11-membered heterocyclic group), more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur (i.e., a 4-8-membered heterocyclic group). Examples of heterocyclic groups include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2-azabicyclo[2.2.2]octanyl, 2,7-diaza-spiro[3.5]nonan-7-yl, 2-oxa-6-aza-spiro[3.3]heptan-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxolane, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimido, and the like.

[0123] In the present application, the term "aryl" as a group or part of other groups means an aryl group having 6 to 18 carbon atoms (preferably 6 to 10 carbon atoms, i.e., C6-C 10For the purposes of the present invention, an aryl group can be a monocyclic, bicyclic, tricyclic or higher ring system, and can also be fused to a carbocyclic or heterocyclic group as defined above, provided that the aryl group is connected to the rest of the molecule through one or more single bonds via atoms on the aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, and the like.

[0124] In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted by an aryl group as defined above.

[0125] In this application, the term "heteroaryl" as a group or part of another group means a 5- to 16-membered conjugated ring system having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Unless otherwise specified in this specification, the heteroaryl group can be a monocyclic, bicyclic, tricyclic or more ring system, and can also be fused to a carbocyclic or heterocyclic group as defined above, provided that the heteroaryl group is connected to the rest of the molecule through one or more single bonds via atoms in the heteroaromatic ring. The nitrogen, carbon or sulfur atoms in the heteroaryl group may be optionally oxidized; the nitrogen atom may be optionally quaternized. For the purposes of the present invention, heteroaryl is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 5- to 10-membered aromatic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur (also referred to as a 5-10-membered heteroaryl group) or a 5- to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur (also referred to as a 5-6-membered heteroaryl group or a 5- or 6-membered heteroaryl group). Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolyl, isoquinolyl, naphthazinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothiophenyl, oxatriol, oxazolyl, cinnolinyl, quinazolinyl, phenylthio, indolizinyl, o-phenanthroline, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridinyl, [1,2,4]triazolo[4,3-b]pyridazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1,2,4]triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrazine, etc.

[0126] As used herein, the term "heteroarylalkyl" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above.

[0127] In this application, the term "absent" means that the two sides of the group defined above are directly connected by a chemical bond. For example, "ABC in which B is absent" means "AC".

[0128] In this application, in Indicates the attachment position of the group R.

[0129] In this application, unless otherwise specified in the claims, "optionally" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes both the occurrence and non-occurrence of the event or situation. For example, "optionally substituted aryl" means that the hydrogen on the aryl group is substituted or not substituted, and the description includes both substituted aryl and unsubstituted aryl. For example, in the absence of explicit listing of substituents, the terms "optionally substituted", "substituted" or "substituted by..." as used herein mean that one or more hydrogen atoms on a given atom or group are independently replaced by one or more, for example, 1, 2, 3 or 4, substituents, and the substituents are independently selected from: deuterium (D), halogen, -OH, oxo (=O), thiol, cyano, -CD3, -C1-C6 alkyl (preferably -C 1-3 C2-C6 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl (preferably C3-C8 cycloalkyl), aryl, heterocyclyl (preferably 3-8 membered heterocyclyl), heteroaryl, aryl-C1-C6 alkyl-, heteroaryl-C1-C6 alkyl-, C1-C6 haloalkyl-, -OC1-C6 alkyl (preferably -OC1-C3 alkyl), -OC2-C6 alkenyl, -O cycloalkyl, -O heterocyclyl, -O aryl, -O heteroaryl, -OC1-C6 alkylphenyl, -C1-C6 alkyl-OH (preferably -C1-C4 alkyl-OH), -C1-C6 alkyl-SH, -C1-C6 alkyl-O-C1-C 6 alkyl, -OC1-C6 haloalkyl, -NH2, -C1-C6 alkyl-NH2 (preferably -C1-C3 alkylNH2), -N(C1-C6 alkyl)2 (preferably N(C1-C3 alkyl)2), -NH(C1-C6 alkyl) (preferably -NH(C1-C3 alkyl)), -N(C1-C6 alkyl)(C1-C6 alkylphenyl), -NH(C1-C6 alkylphenyl), -N(C1-C6 alkyl)(aryl), -NH(aryl), nitro, -C(O)-OH, -C(O)OC1-C6 alkyl (preferably -C(O)OC1-C3 alkyl), -CONR i R ii (where R i and R ii It is H, D and C 1-6 Alkyl, preferably C 1-3alkyl), -NHC(O)(C1-C6 alkyl), -NHC(O)(phenyl), -N(C1-C6 alkyl)C(O)(C1-C6 alkyl), -N(C1-C6 alkyl)C(O)(phenyl), -C(O)C1-C6 alkyl, -C(O)heteroaryl (preferably -C(O)-5-7 membered heteroaryl), -C(O)C1-C6 alkylphenyl, -C(O)C1-C6 haloalkyl, -OC(O)C1-C6 alkyl (preferably -OC(O)C1-C3 alkyl), -S(O)2-C1-C6 alkyl, -S(O)-C1-C6 alkyl, -S(O)2-phenyl, -S(O)2-C1-C6 haloalkyl, -S(O)2NH2, -S(O)2NH(C1-C6 alkyl), -S(O)2NH(phenyl), -NHS(O)2(C1-C6 alkyl), -NHS(O)2(phenyl) and -NHS(O)2(C1-C6 haloalkyl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, aryl, heterocyclic and heteroaryl groups are Each of the following is optionally further substituted by one or more substituents selected from the group consisting of halogen, -OH, oxo (=O), -NH2, cycloalkyl, 3-8 membered heterocyclyl, C1-C4 alkyl, C1-C4 haloalkyl-, -OC1-C4 alkyl, -C1-C4 alkyl-OH, -C1-C4 alkyl-O-C1-C4 alkyl, -OC1-C4 haloalkyl, cyano, nitro, -C(O)-OH, -C(O)OC1-C6 alkyl, -CON(C1-C6 alkyl)2, CONH (C1-C6 alkyl), -CONH2, -NHC(O)(C1-C6 alkyl), -NH(C1-C6 alkyl)C(O)(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2(phenyl), -SO2(C1-C6 haloalkyl), -SO2NH2, -SO2NH(C1-C6 alkyl), -SO2NH(phenyl), -NHSO2(C1-C6 alkyl), -NHSO2(phenyl) and -NHSO2(C1-C6 haloalkyl). When an atom or group is substituted with multiple substituents, the substituents may be the same or different. As used herein, the terms "moiety," "structural moiety," "chemical moiety," "group," and "chemical group" refer to a specific fragment or functional group in a molecule. A chemical moiety is generally considered to be a chemical entity embedded in or attached to a molecule.

[0130] In the present invention, (C1-C4 alkyl)2amino represents an amine substituted with two C1-C4 alkyl groups, for example, wait.

[0131] In the present invention, "plurality" refers to 2, 3 or 4.

[0132] Active ingredient

[0133] As used herein, "compound of the present invention" or "active ingredient" refers to the compound represented by Formula I, and also includes pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, cis-trans isomers, solvates, polymorphs, deuterated forms, or combinations thereof.

[0134] "Stereoisomers" refer to compounds composed of the same atoms, bonded by the same bonds, but having different three-dimensional structures. The present invention is intended to encompass various stereoisomers and mixtures thereof.

[0135] When the compounds of the present invention contain olefinic double bonds, and unless specified otherwise, it is intended that the compounds of the present invention include both E- and Z- geometric isomers.

[0136] "Tautomers" refer to isomers formed when a proton is shifted from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the present invention are intended to be encompassed within the scope of the present invention.

[0137] The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more chiral carbon atoms and may therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral carbon atom may be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the present invention may be prepared using racemates, diastereomers, or enantiomers as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

[0138] Conventional techniques for preparing / isolating individual isomers include chiral synthesis from appropriate optically pure precursors, or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography, see, for example, Gerald Gübitz and Martin G. Schmid (eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; A. M. Stalcup, Chiral Separations, Annu. Rev. Anal. Chem. 3:341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd.), Essex, 1991, 809-816; Heller, Acc. Chem. Res., 1990, 23, 128.

[0139] In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0140] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without the side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, and naphthalene disulfonate. These salts can be prepared by methods known in the art.

[0141] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. The salt derived from organic base includes but is not limited to following salt: primary amines, secondary amines and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.

[0142] Pharmaceutical compositions and methods of administration

[0143] Since the compounds of the present invention have excellent inhibitory activity against methionine adenosyltransferase 2A (MAT2A), the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate MTAP deficiency (MTAP - / - ) types of cancer or tumors (such as those specific tumors listed elsewhere in this article).

[0144] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-500 mg per dose. Preferably, "one dose" is one capsule or tablet.

[0145] As used herein, a "pharmaceutical composition" refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to an organism, thereby facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0146] The compounds of general formula (I) can be used in combination with other drugs known to treat or improve similar conditions. When administered in combination, the original drug's administration method and dosage can remain unchanged, while the compound of formula I is taken simultaneously or subsequently. When the compound of formula I is taken simultaneously with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compound of formula I can be preferably used. Drug combination also includes taking the compound of formula I and one or more other known drugs during overlapping time periods. When the compound of formula I is used in combination with one or more other drugs, the dosage of the compound of formula I or the known drug may be lower than the dosage of each drug taken alone.

[0147] The drugs or active ingredients that can be used in combination with the compound of formula (I) include but are not limited to: chemotherapy drugs (such as docetaxel, paclitaxel, gemcitabine, etc.), PD-1 inhibitors (such as nivolumab, pembrolizumab, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, etc.), CD20 antibodies (such as rituximab, etc.), (such as rituximab, ibrutinib, etc.), KRAS inhibitors (such as AMG510, etc.), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lorlatinib, ocatinib), EGFR inhibitors (such as afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, osimertinib, etc.), VEGFR inhibitors (such as sorafenib, pazopanib, regorafenib, cabozantinib, sunitinib, etc.), PI3K inhibitors agents (such as Dactolisib, Taselisib, etc.), BTK inhibitors (such as Ibrutinib, Tilabrutinib, Acalabrutinib, Zanubrutinib, Vecabuzinib, etc.), HDAC inhibitors (such as Vorinostat, Fimepinostat, Givinostat, Tucidinostat, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, etc.), MEK inhibitors (such as Selumetinib (AZD6244), Trametinib, etc.), ERK inhibitors (such as BVD523, HH2710, etc.), mTOR inhibitors (such as Visusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068), SOS1 inhibitors (such as BI1701963, etc.), PRMT inhibitors or a combination thereof.

[0148] As used herein, the term "pharmaceutically acceptable" refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, that is, the substance can be administered to a subject without causing an adverse biological response or interacting in an adverse manner with any components contained in the composition.

[0149] In this application, "pharmaceutically acceptable carrier" includes but is not limited to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant governmental regulatory authorities as acceptable for human or livestock use.

[0150] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0151] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0152] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0153] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0154] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0155] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0156] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0157] The "tumor (cancer)" of the present invention (such as MTAP-deficient tumor (cancer) or MTAP - / Related tumors (cancers) include, but are not limited to, glioma, mesothelioma, esophageal cancer, bladder cancer, urothelial cancer, pancreatic cancer, melanoma, non-small cell lung cancer, head and neck cancer, sarcoma, bile duct cancer, liver cancer, breast cancer, skin cancer, intestinal cancer, stomach cancer, kidney cancer, urethra cancer, prostate cancer, testicular cancer, uterine cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, multiple myeloma, spinal neurofibroma, astrocytoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma and non-Hodgkin's lymphoma. As used herein, the terms "preventative", "prevention" and "preventing" include reducing the likelihood of a patient developing or worsening a disease or condition.

[0158] As used herein, the term "treat" and other similar synonyms include the following meanings:

[0159] (i) preventing a disease or condition from occurring in a mammal, particularly where such mammal is susceptible to the disease or condition but has not yet been diagnosed as having the disease or condition;

[0160] (ii) inhibiting the disease or condition, i.e., curbing its development;

[0161] (iii) alleviate the disease or condition, that is, cause regression of the disease or condition; or

[0162] (iv) Alleviate the symptoms of the disease or condition.

[0163] As used herein, the terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" refer to an amount of at least one agent or compound sufficient to provide some relief to some degree from one or more symptoms of the disease or condition being treated. This can result in a reduction and / or alleviation of signs, symptoms, or causes of disease, or any other desired change in a biological system. For example, a therapeutically effective amount is the amount of a composition comprising a compound disclosed herein that provides a clinically significant alleviation of symptoms. Techniques such as dose escalation studies can be used to determine the effective amount appropriate for any individual case.

[0164] As used herein, the terms "administer," "administer," "dosing," and the like refer to methods capable of delivering a compound or composition to the desired site for biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injections or infusions), topical administration, and rectal administration. Those skilled in the art are familiar with administration techniques that can be used for the compounds and methods described herein, such as those discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current edition.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

[0165] As used herein, the terms "pharmaceutical combination," "drug combination," "combination therapy," "administration of another therapy," "administration of another therapeutic agent," and the like refer to a pharmaceutical therapy obtained by mixing or combining more than one active ingredient, and include both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that at least one compound described herein and at least one synergistic agent are administered to a patient simultaneously as a single entity or single dosage form. The term "non-fixed combination" means that at least one compound described herein and at least one synergistic agent are administered to a patient simultaneously, in combination, or sequentially at variable intervals as separate entities. This also applies to cocktail therapies, e.g., administration of three or more active ingredients.

[0166] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0167] Compared with the prior art, the present invention has the following beneficial effects:

[0168] (1) The present invention provides a novel compound as shown in Formula I or a pharmaceutically acceptable salt thereof;

[0169] (2) The compounds of the present invention can inhibit MAT2A and can be used to prepare therapeutic agents for MTAP - / - Cancer-related drugs.

[0170] (3) The compounds of the present invention have excellent MTAP deficiency (MTAP - / - ) cell proliferation inhibitory activity.

[0171] (4) The compounds of the present invention have excellent selective cell proliferation inhibitory activity. The compounds of the present application have an effect on MTAP deficiency (MTAP - / - ) cells had significantly better proliferation inhibition activity than MTAP-positive (MTAP) cells. wt ) cells, even in the absence of MTAP (MTAP wt ) cells had basically no proliferation inhibitory activity.

[0172] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which no specific conditions are specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0173] Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial channels.

[0174] In each embodiment, 1H NMR spectra were recorded on a BRUKER AVANCE NEO 400 MHz nuclear magnetic resonance instrument, and chemical shifts are expressed in δ (ppm). Liquid chromatography-mass spectrometry (LCMS) spectra were recorded on Shimadzu LC-20AD, SIL-20A, CTO-20AC, SPD-M20A, CBM-20A, and LCMS-2020 mass spectrometers. Preparative HPLC separations were performed using a Gilson-281 liquid chromatograph.

[0175] Example 1 Synthesis of Compound 1

[0176] The synthetic route of compound 1 is as follows:

[0177] (1) Compound 1-1 (5 g, 21.36 mmol) was added to thionyl chloride (15 mL) and heated under reflux for two hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in acetic acid (30 mL). Anhydrous hydrazine (2.89 mL, 92.90 mmol) was added and heated under reflux at 120°C overnight. The reaction solution was directly concentrated to dryness and added to water (20 mL) to precipitate a solid. The solid was filtered and the filter cake was filtered under reduced pressure and dried under vacuum overnight to obtain compound 1-2. MS-ESI [M+H] + , calculated value 231, measured value 231.

[0178] (2) Compound 1-2 (3 g, 13.03 mmol) was dissolved in phosphorus oxychloride (30 mL), and the mixture was stirred at 100°C overnight. The reaction solution was concentrated under reduced pressure to remove phosphorus oxychloride. The crude oil was slowly added dropwise to ice water (50 mL), stirred thoroughly, and adjusted to pH = 8 with 2 mol / L sodium hydroxide aqueous solution. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was freed from the solvent under reduced pressure. Compound 1-3 was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 1-3. MS-ESI [M+H] + , calculated value 267, measured value 267.

[0179] (3) Methylamine hydrochloride (379.28 mg, 5.62 mmol) and sodium carbonate (1964.76 mg, 18.54 mmol) were added to a solution of compound 1-3 (1500 mg, 5.62 mmol) in N,N-dimethylformamide (20 mL), and the mixture was stirred at 120°C overnight. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:4) to obtain compound 1-4. MS-ESI [M+H] + , calculated value 262, measured value 262.

[0180] (4) Compound 1-5 (61.16 mg, 0.45 mmol), sodium carbonate (76.97 mg, 0.73 mmol) and bis(diphenylphosphino)ferrocenepalladium dichloride (26.94 mg, 0.04 mmol) were added to a solution of compound 1-4 (95 mg, 0.36 mmol) in 1,4-dioxane (4 mL) and water (1 mL). The mixture was stirred at 110°C overnight under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the crude product was purified by high performance liquid chromatography (Puningtech-Pntulips-C18-5μm-21.2×150 mm, A: 0.05% trifluoroacetic acid / water B: acetonitrile, 0-32% B) to obtain compound 1. MS-ESI [M+H] + , calculated value 319, measured value 319. 1 H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.95-8.73(m,2H),8.57(d,J=8.7Hz,1H),8.01( s,1H),7.76(s,1H),7.67-7.46(m,1H),3.24(d,J=3.5Hz,3H),2.36(d,J=15.8Hz,3H).

[0181] Example 2 Synthesis of Compound 2

[0182] The synthetic route of compound 2 is as follows:

[0183] Compound 2-1 (56.mg, 0.36mmol), sodium carbonate (76.97mg, 0.73mmol) and bis(diphenylphosphino)ferrocenepalladium dichloride (26.94mg, 0.04mmol) were added to a solution of compound 1-4 (95mg, 0.36mmol) in 1,4-dioxane (4mL) and water (1mL). The mixture was stirred at 110°C overnight under nitrogen. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC (Puningtech-Pntulips C18 5μm-21.2×150mm, A: 0.1% formic acid / water B: acetonitrile, 0-47% B) to give compound 2. MS-ESI [M+H] + , calculated value 338, measured value 338. 1 H NMR (400MHz, DMSO-d6) δ8.57(d,J=8.7Hz,1H),8.27(d,J=7.6Hz,1H),8.15-8.01(m ,1H),7.69(d,J=7.6Hz,1H),7.64-7.53(m,3H),7.49(s,1H),3.12(d,J=4.3Hz,3H).

[0184] Example 3 Synthesis of Compound 3

[0185] Synthesize Reference Example 1, using deuterated methylamine instead of methylamine to obtain Compound 3.

[0186] Example 4 Synthesis of Compound 4

[0187] (1) To a solution of compound 1-3 (500 mg, 1.87 mmol) in dimethyl sulfoxide (7 mL) were added 4-methoxybenzylamine (256.86 mg, 1.87 mmol) and sodium carbonate (496.15 mg, 4.68 mmol), and the mixture was stirred at 130°C overnight. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 6%-10%) to obtain compound 4-1. MS-ESI [M+H] + , calculated value 368, measured value 368.

[0188] (2) Compound 1-5 (294.32 mg, 2.15 mmol), sodium carbonate (438.07 mg, 4.13 mmol) and bis(diphenylphosphino)ferrocenepalladium dichloride (245.27 mg, 0.33 mmol) were added to a solution of compound 4-1 (607 mg, 1.65 mmol) in 1,4-dioxane (10 mL) and water (2.2 mL). The mixture was stirred at 110°C overnight under nitrogen protection. The reaction solution was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (methanol / dichloromethane = 2%-3%) to obtain compound 4-2. MS-ESI [M+H] + , calculated value 425, measured value 425.

[0189] (3) Compound 4-2 (400 mg, 0.94 mmol) was dissolved in a mixed solution of trifluoroacetic acid (4 mL) and trifluoromethanesulfonic acid (0.4 mL) at 0°C. The mixture was stirred under nitrogen for 10 minutes. The reaction was monitored by LCMS to determine completion. The reaction solution was concentrated, and the crude product was purified by preparative reverse phase chromatography (Waters-CORTECS C18 2.7 μm-4.6×30 mm; 25 ml / min; 25°C; 0%-100% acetonitrile / 0.05% NH4HCO3 aqueous buffer) to obtain compound 4. MS-ESI [M+H] + , calculated value 305, measured value 305. 1H NMR (400MHz, DMSO-d6) δ8.70-8.52(m,2H),8.25(dd,J=8.8,1.8Hz,1H),7.78(dd,J=7.6,1.8Hz,1H),7.59-7.35(m,4H),2.23(s,3H).

[0190] Example 5 Synthesis of Compound 5

[0191] Synthesize Reference Example 4, using the corresponding pyridine boronic acid to replace 1-5 to obtain compound 5.

[0192] Example 6 Synthesis of Compound 6

[0193] (1) Compound 6-1 (206.60 mg, 0.82 mmol), sodium carbonate (115.28 mg, 1.09 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (92.50 mg, 0.11 mmol) were added to a solution of compound 4-1 (200 mg, 0.54 mmol) in 1,4-dioxane (10 mL) and water (2.2 mL). The mixture was stirred at 110°C overnight under nitrogen protection. The reaction solution was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (methanol / dichloromethane = 2%-3%) to obtain compound 6-2. MS-ESI [M+H] + , calculated value 440, measured value 440.

[0194] (2) A solution of sodium nitrite (29.91 mg, 0.43 mmol) dissolved in water (1 mL) was added dropwise to a solution of compound 6-2 (127 mg, 0.29 mmol) in pyridine hydrogen fluoride (3 mL) at -10°C. After the addition was complete, the reaction was stirred at 20°C for 1 hour. The reaction was monitored by LCMS. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, and concentrated. The crude product was purified by silica gel column chromatography with a gradient (methanol / dichloromethane = 2%-3%) to obtain compound 6-3. MS-ESI [M+H] + , calculated value 443, measured value 443.

[0195] (3) Compound 6-3 (95 mg, 0.21 mmol) was dissolved in a mixed solution of trifluoroacetic acid (4 mL) and trifluoromethanesulfonic acid (0.4 mL) at 0°C. The mixture was stirred under nitrogen for 10 minutes. The reaction was monitored by LCMS to determine completion. The reaction solution was concentrated, and the crude product was purified by preparative reverse phase chromatography (Waters-CORTECS C18 2.7 μm-4.6×30 mm; 25 ml / min; 25°C; 0%-100% acetonitrile / 0.05% NH4HCO3 aqueous buffer) to obtain compound 6. MS-ESI [M+H] + , calculated value 323, measured value 323. 1 H NMR (400MHz, CDCl3) δ8.68(dd,J=8.4,5.6Hz,1H),8.18-8.04(m,2H),7.68(s,1H),7.11(dd,J=8.4,5.6Hz,1H),5.96(s,2H),2.40(s,3H).

[0196] Example 7 Synthesis of Compound 7

[0197] (1) Compound 1-5 (276.41 mg, 2.02 mmol), sodium carbonate (545.77 mg, 5.15 mmol) and bis(diphenylphosphino)ferrocenepalladium dichloride (305.57 mg, 0.41 mmol) were added to a solution of compound 1-3 (550 mg, 2.06 mmol) in 1,4-dioxane (10 mL) and water (2.2 mL). The mixture was stirred at 110°C under nitrogen for 3 hours. The reaction solution was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (methanol / dichloromethane = 2%-3%) to obtain compound 7-1. MS-ESI [M+H] + , calculated value 324, measured value 324.

[0198] (2) Under nitrogen protection, compound 7-1 (249 mg, 0.77 mmol), tetrakis(triphenylphosphine)palladium (177.78 mg, 0.15 mmol), triethylamine (1.28 ml, 9.23 mmol) and formic acid (0.04 ml, 0.92 mmol) were dissolved in N,N-dimethylformamide (3 mL). The mixture was stirred at 110°C for 40 minutes under nitrogen protection. The reaction was monitored by LCMS. The crude product was purified by preparative reverse phase chromatography (Waters-CORTECS-C18-2.7 μm-4.6×30 mm; 25 ml / min; 25°C; 0%-100% acetonitrile / 0.05% NH4HCO3 aqueous buffer) to obtain compound 7. MS-ESI [M+H] + , calculated value 290, measured value 290.1 HNMR (400MHz, CDCl3) δ9.64(d,J=0.8Hz,1H),8.70(dd,J=4.8,1.6Hz,1H),8.17(d,J=8.4Hz,1H),8.09(dd,J=8.4,1.6Hz,1H),7.83-7.80(m,1H),7.66(dd, J =7.6,1.8Hz,1H),7.32(dd,J=7.6,4.8Hz,1H),2.30(s,3H).

[0199] Example 8 Synthesis of Compound 8

[0200] The synthetic route of compound 8 is as follows:

[0201] (1) Compound 8-1 (2 g, 7.60 mmol) was added to thionyl chloride (20 mL), and two drops of dry N,N-dimethylformamide solution were added. The mixture was heated under reflux for two hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in acetic acid (30 mL). Anhydrous hydrazine (1.52 g, 30.41 mmol) was added, and the mixture was heated under reflux at 120°C overnight. The reaction solution was directly concentrated to dryness and then added to water (20 mL) to precipitate a solid. The solid was filtered and the filter cake was dried under vacuum overnight to obtain compound 8-2. MS-ESI [M+H] + , calculated value 259, measured value 259.

[0202] (2) Compound 8-2 (3 g, 13.03 mmol) was dissolved in phosphorus oxychloride (30 mL), and the mixture was stirred at 100°C for 2 hours. The reaction solution was concentrated under reduced pressure to remove phosphorus oxychloride. The crude oil was slowly added dropwise to ice water (50 mL), stirred thoroughly, and adjusted to pH = 8 with 2 mol / L sodium hydroxide aqueous solution. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was freed from the solvent under reduced pressure. Compound 8-3 was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 8-3. MS-ESI [M+H] + , calculated value 295, measured value 295.

[0203] (3) To a solution of compound 8-3 (700 mg, 2.37 mmol) in dimethyl sulfoxide (10 mL) were added p-methoxybenzylamine (324 mg, 2.37 mmol) and sodium carbonate (752 mg, 7.10 mmol), and the mixture was stirred at 130°C overnight. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain 8-4. MS-ESI [M+H] + , calculated value 396, measured value 396.

[0204] (4) Compound 8-4 (230 mg, 0.58 mmol) was dissolved in 1,4-dioxane (5 mL). Potassium cyclopropyltrifluoroborate (103 mg, 0.70 mmol), sodium carbonate (184 mg, 1.74 mmol) and 1,1'-bis(di-cyclohexylphosphino)ferrocenepalladium dichloride (88 mg, 0.13 mmol) were added under nitrogen protection. The mixture was stirred in a microwave at 90°C for 3 hours under nitrogen protection. The reaction was monitored by LCMS to complete. The reaction solution was concentrated and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain 8-6. MS-ESI [M+H] + , calculated value 358, measured value 358.

[0205] (5) Compound 1-5 (61.16 mg, 0.45 mmol), sodium carbonate (71 mg, 0.67 mmol) and bis(diphenylphosphino)ferrocenepalladium dichloride (36.6 mg, 0.04 mmol) were added to a solution of compound 8-6 (80 mg, 0.22 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL). The mixture was stirred at 110°C overnight under nitrogen protection. The reaction solution was concentrated and the crude product was purified by silica gel column chromatography (methanol / dichloromethane = 2%-3%) to obtain 8-7. MS-ESI [M+H] + , calculated value 415 measured value 415.

[0206] (6) Compound 8-7 (50 mg, 0.12 mmol) was dissolved in a mixed solution of trifluoroacetic acid (1 mL) and trifluoromethanesulfonic acid (0.2 mL) at 0°C. The mixture was stirred under nitrogen for 60 minutes. The reaction was monitored by LCMS to determine completion. The reaction solution was concentrated, and the crude product was purified by preparative HPLC (Waters-CORTECS-C18-2.7 μm-4.6×30 mm; 25 ml / min; 25°C; 0%-100% acetonitrile / 0.05% NH4HCO3 aqueous buffer) to obtain compound 8. MS-ESI [M+H] + , calculated value 295, measured value 295.1 H NMR (400MHz, DMSO-d6) δ8.52 (dd, J=4.8, 1.6Hz, 1H), 8.11 (d, J=8.4Hz, 1H), 7.67 (dd, J =7.6,1.6Hz,1H),7.49(dd,J=8.4,7.2Hz,1H),7.39-7.30(m,3H),2.20(s ,3H),2.13(td,J=8.4,4.0Hz,1H),1.08-1.02(m,2H),0.94-0.82(m,2H).

[0207] Example 9 Synthesis of Compound 9

[0208] The synthetic route of compound 9 is as follows:

[0209] (1) Lithium diisopropylamide (2 mol / L, 30.86 mL, 61.73 mmol) was added dropwise to tetrahydrofuran (70 mL) at -70°C, and then compound 9-1 (10 g, 41.15 mmol) was slowly added dropwise to the reaction solution over a period of about 20 minutes. After gradually warming to room temperature and stirring for 1.5 hours, carbon dioxide gas was introduced into the reaction solution and stirred for another hour. The reaction was quenched with 3 mol / L hydrochloric acid, and the pH of the solution was adjusted to 1-2. The mixture was then extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent to obtain compound 9-2.

[0210] (2) Compound 9-2 (8 g, 27.87 mmol) and potassium carbonate (5.78 g, 41.81 mmol) were dissolved in N,N-dimethylformamide (60 mL). Iodomethane (2.49 mL, 30.66 mmol) was added dropwise to the reaction mixture at 0°C, and then stirred at 25°C for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. Purification by column chromatography (petroleum ether:ethyl acetate = 50:1) afforded compound 9-3 as a colorless oil.

[0211] (3) Compound 9-3 (8 g, 26.58 mmol) and N,N-diisopropylethylamine (22.02 mL, 132.88 mmol) were dissolved in methanol (40 mL) and N,N-dimethylformamide (40 mL). Palladium acetate (298.32 mg, 1.33 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.54 g, 2.66 mmol) were added to the reaction solution. The reaction solution was then stirred at 80°C for 16 hours under a carbon monoxide atmosphere. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. Compound 9-4 was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 9-4.

[0212] (4) Compound 9-4 (3.0 g, 10.71 mmol) was dissolved in tetrahydrofuran (15 mL) and water (15 mL). Solid sodium hydroxide (1.285 g, 32.12 mmol) was added to the reaction solution at 0°C. The mixture was then stirred at 25°C for 3 hours. The reaction solution was quenched with 3 mol / L hydrochloric acid at 0-10°C, and the pH of the solution was adjusted to 1-2. The mixture was then extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent to obtain compound 9-5.

[0213] (5) Compound 9-5 (2.3 g, 9.12 mmol) was dissolved in thionyl chloride (20 mL), and two drops of dry N,N-dimethylformamide were added. The mixture was heated under reflux at 80°C for 2 hours under nitrogen. The reaction solution was concentrated to dryness and dissolved and concentrated with toluene (20 mL) three times to obtain crude compound 9-6.

[0214] (6) Compound 9-6 (2.8 g, 9.69 mmol) was dissolved in acetic acid (25 mL), hydrazine hydrate (2.85 g, 48.44 mmol) was added, and the mixture was heated to reflux at 120°C for 12 hours. The reaction solution was directly concentrated to dryness, and water was added to disperse the solid. The solid was filtered, and the filter cake was drained and vacuum dried overnight to obtain a light yellow solid compound 9-7. MS-ESI [M+H] + , calculated value 249, measured value 249.

[0215] (7) Compound 9-7 (2.3 g, 9.27 mmol) was dissolved in phosphorus oxychloride (20 mL) and stirred at 100°C for 2 hours. The reaction solution was directly concentrated to remove the phosphorus oxychloride. The oil was then dissolved in ethyl acetate, and the solution was slowly added dropwise to a sodium bicarbonate aqueous solution with sufficient stirring. The mixture was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. Purification by column chromatography (petroleum ether: ethyl acetate = 8:1) gave compound 9-8 as an off-white solid. MS-ESI [M+H] +, calculated value 285, measured value 285.

[0216] (8) Compound 9-8 (700 mg, 2.46 mmol) was dissolved in N-methylpyrrolidone (7 mL), and then (2,4-dimethoxyphenyl)methylamine (410.6 mg, 2.46 mmol) and N,N-diisopropylethylamine (634.8 mg, 4.91 mmol) were added and stirred at 130°C for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried and concentrated, and then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 9-9. MS-ESI [M+H] + , calculated value 416 measured value 416.

[0217] (9) Compound 9-9 (270 mg, 0.65 mmol) was dissolved in 1,4-dioxane (10 mL) and water (1 mL). 2-Methylarsidine-3-boronic acid (177.8 mg, 1.30 mmol), sodium bicarbonate (136.4 mg, 1.62 mmol) and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (53.2 mg, 0.06 mmol) were added under nitrogen protection. The mixture was stirred at 105°C for 3 hours under nitrogen protection. The reaction solution was poured into water and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried and concentrated, and then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 9-10. MS-ESI [M+H] + , calculated value 473, measured value 473.

[0218] (10) Compound 9-10 (160 mg, 0.34 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) and trifluoromethanesulfonic acid (0.2 mL) were added dropwise to the reaction solution at 0°C. The reaction was stirred at 25°C for 1 hour. The reaction solution was directly concentrated, and the oil was dissolved in dichloromethane. The solution was then slowly added dropwise to an icy sodium bicarbonate aqueous solution and stirred thoroughly. The aqueous solution was adjusted to pH = 8, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. Compound 9 was purified by column chromatography (dichloromethane: methanol = 10:1). MS-ESI [M+H] + , calculated value 323, measured value 323. 1H NMR(400MHz, DMSO-d6)δ8.55(dd,J=1.6,4.8Hz,1H),8.39(d,J=8.8Hz,1H),8.30-8.24(m ,1H),7.73(dd,J=1.6,7.6Hz,1H),7.62(s,2H),7.35(dd,J=5.2,7.6Hz,1H),2.21(s,3H).

[0219] Example 10 Synthesis of Compound 10

[0220] The synthetic route of compound 10 is as follows:

[0221] (1) Compound 10-1 (3.0 g, 11.15 mmol) was dissolved in methanol (30 ml), and thionyl chloride (1.21 ml, 16.73 mmol) was added. The mixture was heated to 70°C and stirred for 2 hours under a nitrogen atmosphere. The reaction was monitored for completion by LCMS. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography using 3%-5% ethyl acetate / petroleum ether to obtain compound 10-2.

[0222] (2) Compound 10-2 (1.50 g, 5.30 mmol) and tributyl(1-ethoxyethylene)tin (2.69 ml, 7.95 mmol) were dissolved in 1,4-dioxane (25 ml). Tetrakis(triphenylphosphine)palladium (1.23 g, 1.06 mmol) was added under a nitrogen atmosphere and stirred at 100°C for 12 hours. The reaction was monitored by LCMS. The reaction solution was poured into water and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried, and concentrated to obtain compound 10-3. MS-ESI [M+H] + , calculated value 275, measured value 275. 1 H NMR (400MHz, CDCl3) δ7.87-7.81(m,1H),7.64-7.59(m,1H),7.52(d,J=8.4Hz,1H),4. 37(d,J=2.8Hz,1H),4.27(d,J=2.8Hz,1H),3.84-3.79(m,5H),1.25(d,J=7.2Hz,3H).

[0223] (3) Compound 10-3 (998 mg, 2.55 mmol) was dissolved in a solution of hydrochloric acid in 1,4-dioxane (4 mol / L, 10 ml) at room temperature and stirred at 25°C for 2 hours. The reaction was monitored for completion by LCMS. The reaction solution was concentrated to obtain crude compound 10-4. MS-ESI [M+H] + , calculated value 247, measured value 247.

[0224] (4) Compound 10-4 (1.0 g, 4.07 mmol) and hydrazine hydrate (1 ml, 20.58 mmol) were dissolved in ethanol (10 ml), heated to 90°C under nitrogen atmosphere, and refluxed with stirring for 2 hours. The reaction was monitored by LCMS. After the reaction solution was concentrated, the crude product was purified by silica gel column chromatography: methanol / dichloromethane = 2%-3% gradient to obtain compound 10-5. MS-ESI [M+H] + , calculated value 229, measured value 229. 1 H NMR (400MHz, CDCl3) δ10.26(s,1H),8.73-8.67(m,1H),8.00(dd,J=8.4,1.8Hz,1H),7.86(d,J=8.4Hz,1H),2.57(s,3H).

[0225] (5) Compound 10-5 (551 mg, 2.41 mmol) was dissolved in phosphorus oxychloride (7 ml), heated to 110°C under nitrogen atmosphere, and refluxed with stirring for 1 hour. The reaction was monitored by LCMS. After the reaction solution was concentrated, the crude product was purified by silica gel column chromatography: methanol / dichloromethane = 5%-7% gradient to obtain compound 10-6. MS-ESI [M+H] + , calculated value 247, measured value 247. 1 H NMR (400MHz, CDCl3) δ8.54 (s, 1H), 8.18 (d, J = 8.4Hz, 1H), 8.11 (dd, J = 8.4, 1.6Hz, 1H), 2.98 (s, 3H).

[0226] (6) Compound 10-6 (100 mg, 0.41 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL). 2-Methylarsidine-3-boronic acid (72.18 mg, 0.53 mmol), sodium carbonate (107.44 mg, 1.01 mmol) and 1,1-bis(diphenylphosphine)dichloroferric palladium (60.16 mg, 0.06 mmol) were added under nitrogen protection. The mixture was stirred at 100 ° C overnight under nitrogen protection. The reaction was monitored by LCMS until completion. After the reaction solution was concentrated, the crude product was purified by silica gel chromatography: methanol / dichloromethane = 5%-7% gradient to obtain the crude compound. The crude product was purified by reverse phase chromatography (Waters-CORTECS-C18-2.7 μm-4.6×30 mm; 25 ml / min; 25° C.; 0%-100% acetonitrile / 0.05% formic acid aqueous buffer) to give compound 10. MS-ESI [M+H] + , calculated value 304 measured value 304. 1H NMR (400MHz, CDCl3) δ8.82-8.64(m,1H),8.35(d,J=8.4Hz,1H),8.14(d,J=8.4Hz,1H) ,7.85(s,1H),7.72(d,J=7.2Hz,1H),7.38(t,J=5.6Hz,1H),3.16(s,3H),2.37(s,3H).

[0227] Example 11 Synthesis of Compound 11

[0228] The synthetic route of compound 11 is as follows:

[0229] Compound 10-6 (100 mg, 0.41 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL). 2-Chlorophenylboronic acid (83.35 mg, 0.53 mmol), sodium carbonate (107.44 mg, 1.01 mmol), and 1,1-bis(diphenylphosphino)dichloroferroni palladium (60.16 mg, 0.06 mmol) were added under nitrogen. The mixture was stirred at 100°C overnight under nitrogen. The reaction was monitored for completion by LCMS. The reaction solution was concentrated and the crude product was purified by silica gel column chromatography using a gradient of methanol:dichloromethane = 1%-2% to obtain the crude compound. The crude product was purified by reverse phase chromatography (Waters-CORTECS-C18-2.7 μm-4.6×30 mm; 25 ml / min; 25°C; 0%-100% acetonitrile / 0.05% NH4HCO3 aqueous buffer) to obtain product 11. MS-ESI[M+H] + , calculated value 323, measured value 323. 1 H NMR (400MHz, CDCl3) δ8.31 (d, J = 8.8 Hz, 1H), 8.11 (dd, J = 8.8, 1.6 Hz, 1H), 7.92-7.86 (m, 1H), 7.63-7.48 (m, 4H), 3.15 (s, 3H).

[0230] Biological Experiment Example 1

[0231] Principle: MAT2A catalyzes the conversion of L-methionine and ATP to S-adenosylmethionine (SAM) and phosphate. Phosphate reacts with sulfuric acid and ammonium molybdate to form malachite green phosphomolybdate for detection.

[0232] Experimental materials: MAT2A enzyme was purchased from BPS (catalog number 71401-1); Tris (hydroxymethylaminomethane) was purchased from Life Science (catalog number 0497); fetal bovine serum (BSA) was purchased from Sigma (catalog number V900933); L-methionine was purchased from Adams (catalog number 1100469); ATP was purchased from Sigma (catalog number A7699); magnesium chloride was purchased from Sigma (catalog number M8266); potassium chloride was purchased from Sigma (catalog number 7447-40-7); polyoxyethylene lauryl ether (Brij35) was purchased from Sigma (catalog number B4184); ethylenediaminetetraacetic acid (EDTA) was purchased from Sigma (catalog number M1644); dimethyl sulfoxide (DMSO) was purchased from Sigma (catalog number D2650); Green was purchased from Enzo (catalog number BML-AK111-0250); 384-well plates were purchased from Corning (catalog number 3765); centrifuge was purchased from Eppendorf (model 5430); microplate reader was purchased from Bio Tek (model Synergy 2); and pipette was purchased from Labcyte (model Echo 550).

[0233] Experimental Methods: Prepare a buffer solution consisting of 50 mM Tris, pH 7.5, 50 mM potassium chloride, 10 mM magnesium chloride, 0.01% Brij-35, 1 mM EDTA, and 0.1% BSA. Test compounds were diluted starting at a final concentration of 10 μM and tested in duplicate at 10 concentrations in 3-fold dilutions. Serial dilutions were performed in a 384-well plate to yield 10 different concentrations at 100x the final concentration. Then, using an Echo550, transfer 250 nL of the solution to a 384-well plate for later use. Add 250 nL of 100% DMSO to each of the negative and positive control wells. Prepare a MAT2A enzyme solution at 1.67x the final concentration using the buffer solution. Add 15 μL of the 1.67x final concentration of the MAT2A enzyme solution to each of the compound and positive control wells; add 15 μL of the buffer solution to the negative control well. Centrifuge at 1000 rpm for 60 seconds, shake to mix, and incubate for 15 minutes. Prepare a substrate mixture solution (substrates are L-methionine and ATP) at 2.5 times the final concentration using buffer. Add 10 μL of the substrate mixture solution at 2.5 times the final concentration to start the reaction. Centrifuge the 384-well plate at 1000 rpm for 60 seconds, shake and mix, and incubate for 150 minutes. Add The reaction was terminated with ELISA Green, centrifuged at 1000 rpm for 60 seconds, and incubated for 15 minutes. OD620 was read and the data processed.

[0234] Experimental data:

[0235] The specific test results are shown in Table 1:

[0236] Table 1 MAT2A IC values ​​of some compounds 50 data

[0237] A represents 0 <IC 50 <200nM, B means 200nM≤IC 50 <1000nM, C means 1000nM≤IC 50 <10000nM, D represents IC 50 ≥10000nM.

[0238] As can be seen from the test data in Table 1, the spirocyclic compound represented by formula I of the present invention has a good inhibitory effect on MAT2A and is useful for the preparation of a drug for preventing or treating MTAP. - / - Potential for drugs related to cancer.

[0239] Biological Experiment Example 2

[0240] HCT116 MTAP - / - and HCT 116MTAP wt Cell proliferation inhibitory activity

[0241] Experimental Principle: HCT116 MTAP - / - Cellular MTAP deficiency and elevated MTA levels; HCT 116MTAP wt These two cell lines were used to determine whether the compounds exhibited synergistic MTA inhibitory activity.

[0242] Experimental materials: HCT116 MTAP - / - and HCT 116 MTAP wtCells were purchased from Horizon; CellTiter-Glo reagent was purchased from Promega (catalog number G7571); RPMI-1640 was purchased from ATCC (catalog number 30-2001); fetal bovine serum (FBS) was purchased from EXCELL (catalog number FND500); penicillin-streptomycin was purchased from Gibco (catalog number 15140-122); 0.25% trypsin-ethylenediaminetetraacetic acid digestion solution (Trypsin-EDTA) was purchased from Gibco (catalog number 25200-072); dimethyl sulfoxide (DMSO) was purchased from Sigma (catalog number D2650); 96-well plates were purchased from Corning (catalog number 3610); incubator was purchased from NuAire (model NU-5700E); inverted microscope was purchased from Nikon (model TS-100); and automatic cell counter was purchased from Life technologies (model Countess). II); the microplate reader was purchased from PerkinElmer (model: Envision); and the data processing software was GraphPad Prism 5.0.

[0243] Test method: HCT116 MTAP in the logarithmic growth phase - / - or HCT116 MTAP wt The cells were resuspended in growth medium (RPMI-1640 + 10% FBS) and diluted to the target density (5000 / mL). 100 μL of the cell suspension was seeded into a 96-well plate per well; the suspension was incubated overnight in a 2% incubator at 37°C. The culture medium served as the background control. The cells were starved with 80 μL of serum-free culture medium for 4 hours. The test compound was dissolved in DMSO and prepared into a stock solution with a concentration of 10 mmol / L. The stock solution was first diluted to 2 mmol / L (200×) with DMSO, and then diluted 3-fold in a series of 10 concentrations. 3 μL of the above solution of each concentration was taken and diluted with 297 μL of growth medium (2×). Then 80 μL / well was added to the 96-well plate seeded with cells. The cells with the test compound were placed in a 37°C, 5% CO2 incubator and incubated for 120 hours. The 96-well plate was balanced at room temperature, 40 μL of CellTiter-Glo reagent was added to each well, mixed on a vortexer for 2 minutes, and incubated at room temperature for 60 minutes. The luminescence value was read using an EnVision microplate reader, and the IC value of the compound was calculated using GraphPad Prism 5.0 software. 50 , the results are shown in Table 2.

[0244] Table 2

[0245] A represents 0 <IC 50<100nM, B means 100nM≤IC 50 <1000nM, C means 1000nM≤IC 50 <10000nM, D represents IC 50 ≥10000nM, ND means not detected.

[0246] Biological Example 3

[0247] Proliferation inhibition of various tumor cells with wild-type or deleted MTAP genes

[0248] Principle: Human tumor cell lines HCC15, NCI-H2052, LN18, NCI-H838, LU99, DOHH2, HT-1080, MKN45, THP-1, MCF7, Mia-Paca2, U87-MG, and UMUC3 are all MTAP gene-deficient cell lines. NCI-H1944, ASPC-1, U251, and HT-1376 are MTAP gene wild-type cell lines. The compounds of this invention can inhibit the proliferation of MTAP-deficient cell lines by binding to MAT2A, but have little inhibitory effect on MTAP wild-type cells.

[0249] Experimental materials: The cell lines used in the above experiments are detailed in Table 3; CellTiter-GloR was purchased from Promega (Cat. No. G7571); Luminescent Cell Viability Detection Kit was purchased from VEKY-BIO (Cat. No. A2010003N); RPMI-1640 was purchased from Viva cell (Cat. No. C3010-0500); DMEM was purchased from Viva cell (Cat. No. C3113-0500); EMEM was purchased from Vicente (Cat. No. 320-005-CL); fetal bovine serum (FBS) was purchased from Biosera (Cat. No. FB-1058 / 500); horse serum (FBS) was purchased from Gibco (Cat. No. 16050-122); NEAA was purchased from Vicente (Cat. No. 321-011-EL); penicillin-streptomycin was purchased from BasalMedia (Cat. No. S110JV); sodium Pyruvate was purchased from McLean (catalog number P6033); 0.25% trypsin-ethylenediaminetetraacetic acid digestion solution (Trypsin-EDTA) was purchased from BasalMedia (catalog number S310KJ); dimethyl sulfoxide (DMSO) was purchased from Sinopharm (catalog number 30072418); 96-well plates for 2D culture (for H838 cell line only) were purchased from Corning (catalog number 3610); 96-well plates for 3D culture (for all cell lines except H383 cell line) were purchased from Corning (catalog number 3707); incubator was purchased from PHCbi (model MCO-18AC); inverted microscope was purchased from Mingmei (catalog number MI52-0); automatic cell counter was purchased from BodBoge (model JSY-SC-031N); microplate reader was purchased from PerkinElmer (model Envision); data processing software was GraphPad Prism 8.0.

[0250] Experimental method: Resuspend the above cells in the logarithmic growth phase in growth medium and dilute to an appropriate density (about 6250 / mL). Inoculate 80 μL of the above cell suspension into a 96-well plate per well; incubate overnight in a 37°C, 5% CO2 incubator. The culture medium serves as the background control group. Dissolve the compound to be tested in DMSO and prepare a stock solution with a concentration of 10 mmol / L. First, dilute the stock solution to 2 mmol / L with DMSO, and then dilute it 5-fold for a total of 9 concentrations. Take 2 μL of the above solution of each concentration and dilute it with 78 μL of growth medium respectively. Then add 20 μL / well to the 96-well plate inoculated with cells. Place the cells with the test compound in a 37°C, 5% CO2 incubator and incubate for 6 days, change the medium, and continue incubation for up to 10 days. A 96-well plate was balanced at room temperature, and 100 μL of Luminescent Cell Viability Detection reagent or 25 μL CellTiter-Glo reagent was added to each well. The plates were incubated at room temperature for 10 minutes. The luminescence values ​​were read using an EnVision microplate reader, and the IC values ​​of the compounds were calculated using GraphPad Prism 8.0 software. 50 The specific test results are shown in Table 4.

[0251] Table 3: Cell line name, cancer, cell source and culture medium information

[0252] Table 4: Effect of compound 4 on the proliferation of cell lines with various MTAP gene phenotypes

[0253] A represents 0 <IC 50 <100nM, B means 100nM≤IC 50 <1000nM, C means 1000nM≤IC 50 <10000nM, D represents IC 50 ≥10000nM, ND means not detected, NT means not tested.

[0254] The applicant declares that the present invention illustrates the spirocyclic compounds, pharmaceutical compositions containing the same, and their uses through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. All documents mentioned in the present invention are cited as references in this application, just as each document is cited as a reference individually. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the scope of protection and disclosure of the present invention.

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated form or a combination thereof, in, R 1 is selected from the group consisting of hydrogen, hydroxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, optionally substituted 6-10 membered aryl, optionally substituted 5-10 membered heteroaryl, -L 1 -R 4 and-NR 5 R 6 ; R 1 In the above, "optionally substituted" means that the specified group is unsubstituted or replaced by one or more R 1s replaced, and R 1s Each is independently selected from the following group: halogen, hydroxy, amino, cyano, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 haloalkynyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy C1-C6 alkyl-, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-10 membered carbocyclic group, L 1 Selected from the group consisting of -O-, -S-, -SO-, -SO2- and -CO-; R 4 is selected from the group consisting of an optionally substituted C1-C6 alkyl, an optionally substituted 3-10 membered carbocyclyl, an optionally substituted 4-8 membered heterocyclyl, an optionally substituted 6-10 membered aryl, and an optionally substituted 5-10 membered heteroaryl; R 4 In the above, "optionally substituted" means that the specified group is unsubstituted or replaced by one or more R 4s replaced, and R 4s Each is independently selected from the following group: halogen, hydroxy, amino, cyano, oxo, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 haloalkynyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy C1-C6 alkyl, amino C1-C6 alkyl, 3-10 membered carbocyclyl, 3-10 membered carbocyclyloxy, 4-8 membered heterocyclyl, 4-8 membered heterocyclyloxy, 6-10 membered aryl, 5-10 membered heteroaryl, R 5 Selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and 3-10 membered carbocyclyl; R 6 is selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 6-10 membered aryl, optionally substituted 5-10 membered heteroaryl, R 6 In the above, "optionally substituted" means that the specified group is unsubstituted or replaced by one or more R 6s replaced, and R 6s Each is independently selected from the group consisting of deuterium, halogen, hydroxy, amino, cyano, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 haloalkynyl, optionally substituted by one or more R 8 substituted 3-10 membered carbocyclic group, optionally substituted by one or more R 8 substituted 3-10 membered carbocyclyloxy, optionally substituted with one or more R 8 substituted 4-8 membered heterocyclic group, optionally substituted by one or more R 8 Substituted 4-8 membered heterocyclyloxy, C1-C6 alkylamino, (C1-C6 alkyl)2amino, C1-C6 alkoxy-C1-C6 alkyl, aminoC1-C6 alkyl, Optionally one or more R 9 substituted 6-10 membered aryl and optionally substituted by one or more R 9 substituted 5-10 membered heteroaryl; R 2 is selected from the group consisting of halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, -L 2 -R 10 and-NR 11 R 12 ; R 2 In the above, "optionally substituted" means that the specified group is unsubstituted or replaced by one or more R 2s replaced, and R 2s Each is independently selected from the group consisting of halogen, cyano, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and 3-10 membered carbocyclyl; R 3 is selected from the group consisting of hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, -L 2’ -R 10’ and-NR 11’ R 12’ ; R 3 In the above, "optionally substituted" means that the specified group is unsubstituted or replaced by one or more R 3s , and R 3s Each is independently selected from the group consisting of halogen, cyano, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and 3-10 membered carbocyclyl; L 2 and L 2’ Each independently selected from the group consisting of -O-, -S-, -SO-, -SO2- and -CO-; R 10 and R 10’ Each is independently selected from the group consisting of an optionally substituted C1-C6 alkyl group, an optionally substituted 3-10 membered carbocyclyl group, an optionally substituted 4-8 membered heterocyclyl group, an optionally substituted 6-10 membered aryl group, and an optionally substituted 5-10 membered heteroaryl group; R 10 and R 10’ In the above, "optionally substituted" means that the specified group is unsubstituted or replaced by one or more R 10s replaced, and R 10s Each is independently selected from the group consisting of halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-10 membered carbocyclyl, 4-8 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl; R 11 and R 11’ Each independently selected from the group consisting of hydrogen and C1-C6 alkyl; R 12 and R 12’ Each is independently selected from the group consisting of an optionally substituted C1-C6 alkyl group, an optionally substituted 3-10 membered carbocyclyl group, an optionally substituted 4-10 membered heterocyclyl group, an optionally substituted 6-10 membered aryl group, an optionally substituted 5-10 membered heteroaryl group, R 12 and R 12’ In the above, "optionally substituted" means that the specified group is unsubstituted or replaced by one or more R 12s replaced, and R 12s Each is independently selected from the group consisting of halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-10 membered carbocyclyl and 4-8 membered heterocyclyl; X 3 Selected from the group consisting of: CH and N; R X Selected from the group consisting of methyl, ethyl, 3-4 membered carbocyclyl, halomethyl or halogen; R Y Selected from the group consisting of hydrogen, methyl, halomethyl or halogen; X 1 Selected from the following group: CR 13 and N; X 2 Selected from the following group: CR 14 and N; R 13 and R 14 R is independently selected from the group consisting of hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-8 membered heterocyclyl; 13 and R 14 In the above, "optionally substituted" means that the specified group is unsubstituted or replaced by one or more R 13s or R 14s replaced, and R 13s and R 14s are independently selected from the group consisting of halogen and oxo (=O); with the additional proviso that when R X and R 2 At the same time, X 1 CR 13 When R 13 Not for chlorine; Each R 7 Each is independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-10 membered carbocyclyl, 4-8 membered heterocyclyl, amino, C1-C6 alkylamino, di(C1-C6 alkyl)amino, 6-10 membered aryl and 5-10 membered heteroaryl; Each R 8 Each is independently selected from the group consisting of hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl or hydroxy C1-C6 alkyl; Each R 9 Each is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated form or a combination thereof, characterized in that: R 1 is selected from the group consisting of hydrogen, hydroxy, optionally substituted C1-C6 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, -OR 4 and-NR 5 R 6 ; R 1 The term "optionally substituted" means that the specified group is unsubstituted or replaced by one or more R 1s replaced, and R 1s Each is independently selected from the group consisting of halogen, hydroxy, amino, cyano, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy and C1-C6 haloalkoxy.

3. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated form or a combination thereof, characterized in that: R 2 is selected from the group consisting of halogen, optionally substituted C1-C6 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, and -L 2 -R 10 ; R 2 In the above, "optionally substituted" means that the specified group is unsubstituted or replaced by one or more R 2s replaced, and R 2s Each is independently selected from the group consisting of halogen, cyano, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and 3-8 membered carbocyclyl; R 3 is selected from the group consisting of hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, -L 2’ -R 10’ ; R 3 In the above, "optionally substituted" means that the specified group is unsubstituted or replaced by one or more R 3s replaced, and R 3s Each is independently selected from the group consisting of halogen, cyano, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and 3-8 membered carbocyclyl; R 10 and R 10’ Each is independently selected from the following group: optionally substituted C1-C6 alkyl, optionally substituted 3-8 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl; R 10 and R 10’ In the above, "optionally substituted" means that the specified group is unsubstituted or replaced by one or more R 10s replaced, and R 10s Each is independently selected from the following group: halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-8 membered carbocyclyl, 4-8 membered heterocyclyl; 4. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated form or a combination thereof, characterized in that: R X Selected from the group consisting of methyl, ethyl, halomethyl and halogen; X 1 Selected from the following group: CR 13 and N; X 2 Selected from the following group: CR 14 and N; R 13 and R 14 Each is independently selected from the group consisting of hydrogen, halogen, cyano, C1-C4 alkyl or C1-C4 haloalkyl; with the additional condition that when R X and R 2 At the same time, X 1 CR 13 When R 13 Not for chlorine; 5. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated form or combination thereof, characterized in that: R X is methyl or halogen; R Y is hydrogen, methyl or halogen.

6. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated form or combination thereof, characterized in that: R 1 Selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl and -NR 5 R 6 ; Among them, R 5 is hydrogen, and R 6 is selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, and optionally substituted 5-10 membered heteroaryl; R 6 In the above, "optionally substituted" means that the specified group is unsubstituted or replaced by one or more R 6s replaced, and R 6s is deuterium or C1-C6 alkyl; R 2 is selected from the group consisting of halogen, optionally substituted C1-C6 alkyl, and optionally substituted 3-10 membered carbocyclyl; R 2 wherein the "optionally substituted" is as described in claim 1; R 3 is hydrogen or -L 2’ -R 10’ Among them, L 2’ is -O- and R 10’ is methyl; X 1 CR 13 ; X 2 CR 14 ; X 3 is N; R 13 and R 14 Each is independently selected from the group consisting of hydrogen, halogen, cyano, C1-C4 alkyl or C1-C4 haloalkyl; R X is methyl, halogen or cyclopropyl; R Y is hydrogen, methyl or halogen.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated substance or a combination thereof, characterized in that: The compound is selected from the following Table A: Table A 8. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: (1) a therapeutically effective amount of a compound as claimed in any one of claims 1 to 7, or one or more of its pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, cis-trans isomers, solvates, polymorphs and deuterated substances as an active ingredient; and (2) Optionally, a pharmaceutically acceptable carrier.

9. A compound according to any one of claims 1 to 7, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph or deuterated form or the pharmaceutical composition according to claim 8 for use in the preparation of a drug for preventing or treating MTAP - / - Use in medicine for treating related cancers.

10. The use according to claim 9, characterized in that The cancer is selected from the group consisting of glioma, mesothelioma, esophageal cancer, bladder cancer, urothelial cancer, pancreatic cancer, melanoma, non-small cell lung cancer, head and neck cancer, sarcoma, bile duct cancer, liver cancer, breast cancer, skin cancer, intestinal cancer, gastric cancer, kidney cancer, urethral cancer, prostate cancer, testicular cancer, uterine cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, multiple myeloma, spinal neurofibroma, astrocytoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma and non-Hodgkin's lymphoma.

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